Defects in a single gene can result in two immune
system disorders that leave affected individuals vulnerable
to frequent or unusually severe infections, according
to new findings reported in the August issue of Nature
Genetics. The discovery may lead to new diagnostic tests
for these two inherited conditions — immunoglobulin A
(IgA) deficiency and common variable immunodeficiency
(CVID). Currently, doctors diagnose the conditions by
measuring immunoglobulin levels and excluding other
causes for lowered immunoglobulin levels; there are
no specific tests to detect the two disorders.

A deficiency of IgA — an important type of infection-fighting
antibody found in tears, saliva and other secretions — affects
1 in 600 people in the western world; CVID is less common
but more severe. Both conditions result in a person
being more susceptible to pneumonia and to recurring
infections of the ear, sinus and gastrointestinal tract.
People with CVID also have an increased risk of developing
cancers that affect B cells, cells that produce antibodies.
Furthermore, IgA deficiency and CVID can predispose
to autoimmune diseases, where the immune system turns
against the body’s own tissues and organs.

“Most cases of CVID and IgA deficiency are of unknown
cause,” notes Josiah Wedgwood, M.D., Ph.D., of the Clinical
Immunology Branch of the National Institute of Allergy
and Infectious Diseases (NIAID), the component of the
National Institutes of Health that funded the study. “To
find a specific molecular defect that is the apparent
cause of illness in a substantial subset of individuals
with these two diseases is extremely important. Not
only will this finding enable us to better diagnose
these patients, it provides clues to key biochemical
pathways that can lead to immunodeficiencies.”

The study was led by Raif Geha, M.D., and Emanuela
Castigli, Ph.D., of the Children’s Hospital Boston.
The Boston team found specific mutations in a gene known
as TACI, which plays a specific role in orchestrating
the immune response. Defects in TACI were found in 4
of 19 unrelated patients with CVID and in 1 of 16 unrelated
patients with IgA deficiency. None of 50 healthy people
they studied had a TACI mutation. The scientists believe
that it is likely that as yet unidentified genetic defects
underlie CVID and IgA deficiency in those cases where
TACI was not mutated.

When the scientists further examined four of the five
individuals with TACI mutations, they found all four
had relatives with the same mutations. Eleven of the
12 identified relatives with CVID or IgA deficiency
reported a history of recurrent infections and were
also found to have low levels of IgA and/or low levels
of another type of antibody, immunoglobulin G (IgG).

TACI mutations interfere with two aspects of the immune
response that involve maturation of B cells. Normally,
TACI triggers B cells to switch from making immunoglobulin
M (IgM), an antibody produced early in the immune response,
to making other antibodies such as IgA and IgG. More
important, TACI signals B cells to produce antibodies
against specific invading bacteria and viruses.

Because TACI mutations are genetically dominant, a
person with TACI mutations in one of the two TACI genes
he or she inherits is unable to mount a strong antibody
response. Each child of a person so affected has a 50
percent chance of inheriting the mutation and being
predisposed to IgA deficiency and CVID.

“A test for TACI defects would enable the diagnosis
of more children and their relatives with these immune
deficiencies,” says Dr. Geha, senior author of the study
and the James Gamble Professor of Pediatrics at Harvard
Medical School. “Many children who are sick with these
disorders are now missed, because they can have normal
IgA and IgG levels, yet they still have poor antibody
responses and get the same bacterial and virus infections
again and again.”

But the gene discovery will not immediately change
treatment strategies, notes Dr. Geha. “For the time
being, therapy still consists of prophylactic antibiotics
or intravenous immunoglobulin infusions every three
weeks,” he says.

NIAID is a component of the National Institutes
of Health, an agency of the U.S. Department of Health
and Human Services. NIAID supports basic and applied
research to prevent, diagnose and treat infectious
diseases such as HIV/AIDS and other sexually transmitted
infections, influenza, tuberculosis, malaria and illness
from potential agents of bioterrorism. NIAID also
supports research on transplantation and immune-related
illnesses, including autoimmune disorders, asthma
and allergies.

News releases, fact sheets and other NIAID-related
materials are available on the NIAID Web site at http://www.niaid.nih.gov.

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